DSIMÅrsmødet 6. marts 2009

Arvelighed og Rheumatoid artrit

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Reumatologiske sygdomme

• En heterogen gruppe af sygdomme, der almindeligvis afficerer bevægeapparatet (bevægeapparatets medicinske sygdomme)

Reumatologi• Degenerative sygdomme

• Inflammatoriske sygdomme

• Bløddelsgigt (regionale smertetilstande)

• Bindevævssygdomme

• Generaliserede smertetilstande

• Idrætsskader

Reumatologi

• Inflammatoriske sygdomme– Polyartritter– Oligoartritter– Monartritter– Spondylartritter– Infektionsrelaterede artritter– Krystalartritter– Sjældne artropatier

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Pedersen JK, Svendsen AJ, Horslev-Petersen K. Incidence of Rheumatoid Arthritis in the Southern part of Denmark from 1995 to 2001. Open Rheumatol J 2007; 1:18-23. 2007 Nov 27.:18-23.

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Michou L, Rat AC, Lasbleiz S, Bardin T, Cornelis F. Prevalence and distribution of autoimmune diseases in 368 rheumatoid arthritis families. J Rheumatol 2008; 35(5):790-796.

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Jones MA, Silman AJ, Whiting S, Barrett EM, Symmons DP. Occurrence of rheumatoid arthritis is not increased in the first degree relatives of a population based inception cohort of inflammatory polyarthritis. Ann Rheum Dis 1996; 55(2):89-93.

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Danish1965

UK-ARC 1970 Finnish1986

Australian1992

UK-ARC 1993 Danish2002

Twin sources

Nation-wide + - + + + +

Population based Birth cohort + - + - - +

ARA 87 - - - + + +

Number of twin pairs included MZ 16 20 73 14 91 13

DZ 31 73 173 9 112 36

MZ proportion % Same-sexed 57(49-64)

--

30(24-36)

--

--

--

Mix-sexed --

22(14-31)

--

61(39-80)

45(38-52)

27(15-41)

Concordance rates% Pairwise MZ - 30(12-54) - 21(5-51) 15(9-25) -

Pairwise DZ - 5(2-13) - 0(0-34) 4(1-9) -

Probandwise MZ 50(38-64) - 22(14-33) - - 0(0-24)

Probandwise DZ 5(2-13) - 7(4-11) - - 9(2-24)

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CHARACTERIZING THE QUANTITATIVE GENETIC CONTRIBUTIONTO RHEUMATOID ARTHRITIS USING DATA FROM TWINS

Conclusion. Genetic factors have a substantialcontribution to RA in the population, accounting for60% of the variation in liability to disease. Althoughtempered by power considerations, there is no evidencein these twin data that the overall genetic contributionto RA differs by sex, age, age at disease onset, anddisease severity.

MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43(1):30-37.

Gregersen, P. K.et al. The shared epitope hypothesis. An approach to understanding the

molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987.

The contribution of HLA to rheumatoid arthritis

• Estimates on both population and hospital based data suggest that HLA genes accounts for 37% of genetic contribution to RA

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Deighton CM, Walker DJ, Griffiths ID, Roberts DF. The contribution of HLA to rheumatoid arthritis. Clin Genet 1989; 36:178-182.

17Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447(7145):661-678.

Genetic risk factors

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Genes Odds ratio

Heterozygote Homozygote

MHC class II antigens 2.36 (1.97-2.84) 5.21(4.31-6.30)

PTPN22 1.98(1.72-2.27) 3.32(1.93-5.69)

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447(7145):661-678.

RA associerede autoantistoffer

• Reumafaktorer (1940)• Anti-filaggrin antistoffer (AFA)

– Antiperinukleære antistoffer (1964)– Antikeratin antistoffer (1979)

• Anti-CCP antistoffer (2000)

Padyukov, L.et al. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.

Arthritis Rheum. 2004.

21Vittecoq O et al. Klemmer N. Smoking and inflammatory diseases. Best Pract Res Clin Rheumatol 2008; 22(5):923-935.

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Vittecoq O et al. Klemmer N. Smoking and inflammatory diseases. Best Pract Res Clin Rheumatol 2008; 22(5):923-935.

Rheumatoid arthritis

• We expect more subdivisions to be developed soon when additional biomarkers as well as additional clinically relevant features are identified that associate with different genetic polymorphisms and environmental triggers.

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